Limits...
Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery

View Article: PubMed Central - PubMed

ABSTRACT

Tacrolimus (FK506), an effective immunosuppressant for treating inflammatory skin diseases, hardly penetrates into and through the skin owing to its high hydrophobicity and molecular weight. The aim of this study was to develop a hybrid system based on nicotinamide (NIC) and nanoparticles (NPs) encapsulating FK506, such as FK506–NPs–NIC, for facilitating percutaneous delivery, which exploited virtues of both NIC and NPs to obtain the synergetic effect. Solubility and percutaneous permeation studies were carried out. The results showed that NIC could increase the solubility and permeability of FK506 and that 20% (w/v) NIC presented higher FK506 permeability and was thus chosen as the hydrotropic solution to solubilize FK506 and prepare FK506–NPs–NIC. Hyaluronic acid (HA) was chemically conjugated with cholesterol (Chol) to obtain amphiphilic conjugate of HA–Chol, which self-assembled NPs in 20% NIC solution containing FK506. The particle size, zeta potential, and morphology of NPs were characterized. The encapsulation efficiency and in vitro percutaneous permeation of NPs were evaluated in the presence and absence of NIC. The results demonstrated that hydrotropic solubilizing FK506 was readily encapsulated into NPs with a higher encapsulation efficiency of 79.2%±4.2%, and the combination of NPs with NIC exhibited a significantly synergistic effect on FK506 deposition within the skin (2.39±0.53 μg/cm2) and penetration through the skin (13.38±2.26 μg/cm2). The effect of the combination of NPs with NIC on drug permeation was further visualized by confocal laser scanning microscope through in vivo permeation studies, and the results confirmed that NPs–NIC synergistically enhanced the permeation of the drug into the skin. The cellular uptake performed in HaCaT cells presented a promoting effect of NPs on cellular uptake. These overall results demonstrated that HA–Chol–NPs–NIC can synergistically improve the percutaneous delivery of FK506, and it is a novel potential strategy based on a nano-sized carrier for FK506 to treat skin diseases.

No MeSH data available.


Related in: MedlinePlus

In vitro skin percutaneous studies of FK506 from different vehicles.Notes: Data represent mean ± SD, n=4 per group. *Significantly different (P<0.05) in comparison with FK506 aqueous suspension. **Significantly different (P<0.05) in comparison with Protopic, 0.1%, w/w. ***Significantly different (P<0.05) in comparison with FK506–NPs. ****Significantly different (P<0.05) in comparison with FK506–NIC solution. The concentration of FK506 in each formulation was 1 mg/mL.Abbreviations: FK506, tacrolimus; FK506–HA–Chol–NPs, tacrolimus-loaded hyaluronic acid–cholesterol nanoparticles; FK506–HA–Chol–NPs–NIC, tacrolimus-loaded hyaluronic acid–cholesterol nanoparticles containing nicotinamide; FK506–NIC complex, tacrolimus–nicotinamide complex; FK506–NPs, tacrolimus–nanoparticles complex; h, hours; SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4998035&req=5

f5-ijn-11-4037: In vitro skin percutaneous studies of FK506 from different vehicles.Notes: Data represent mean ± SD, n=4 per group. *Significantly different (P<0.05) in comparison with FK506 aqueous suspension. **Significantly different (P<0.05) in comparison with Protopic, 0.1%, w/w. ***Significantly different (P<0.05) in comparison with FK506–NPs. ****Significantly different (P<0.05) in comparison with FK506–NIC solution. The concentration of FK506 in each formulation was 1 mg/mL.Abbreviations: FK506, tacrolimus; FK506–HA–Chol–NPs, tacrolimus-loaded hyaluronic acid–cholesterol nanoparticles; FK506–HA–Chol–NPs–NIC, tacrolimus-loaded hyaluronic acid–cholesterol nanoparticles containing nicotinamide; FK506–NIC complex, tacrolimus–nicotinamide complex; FK506–NPs, tacrolimus–nanoparticles complex; h, hours; SD, standard deviation.

Mentions: As reported in previous studies, the application of NPs as the vehicle for percutaneous drug delivery achieved more retention of drugs in the skin for prolonging the residence time and targeting upper layer of skin.43,44 In the present study, we used HA–Chol–NPs as the carrier and NIC as the hydrotrope to prepare FK506–HA–Chol–NPs–NIC system and evaluate their effects on FK506 permeation into and across the skin. The cumulative permeated amount of FK506 was plotted versus time, and the retention of FK506 in the skin is shown in Figure 5 and Table 4. The commercial preparation (Protopic, 0.1%, w/v) and 0.1% (w/v) FK506 aqueous suspension were taken as the reference group and control group, respectively. As shown in Figure 5 and Table 4, the FK506 permeation from the NIC complex or HA–Chol–NPs was higher than that from Protopic or suspension after 24 hours of permeation, and there was no significant difference between Protopic and suspension (P>0.05). The cumulative permeated amount of FK506 from NPs or NIC complex was, respectively, 1.53-fold or 1.70-fold as that of Protopic, and the skin retention of FK506 from NPs or NIC complex was, respectively, 2.05-fold or 4.17-fold as that of Protopic. What is more, FK506 from NPs–NIC showed the highest permeation at all time points as compared with NPs or the NIC complex group. The cumulative permeated amount of FK506 was 13.38±2.26 μg/cm2 after 24 hours of permeation, which was significantly higher than that of the NIC complex, 6.60±2.27 μg/cm2 (P<0.05), or NPs alone, 5.96±1.05 μg/cm2 (P<0.05), and the FK506 retention in the skin from NPs–NIC presented the highest retention (2.39±0.53 μg/cm2) than NPs (0.84±0.14 μg/cm2) or the NIC complex (1.71±0.32 μg/cm2; P<0.05). The results indicated that either NPs carrier or NIC hydrotropy could enhance the permeation of FK506, and the combination of HA–Chol–NPs with NIC could synergistically enhance the permeation of FK506 into and through the skin.


Combination of hydrotropic nicotinamide with nanoparticles for enhancing tacrolimus percutaneous delivery
In vitro skin percutaneous studies of FK506 from different vehicles.Notes: Data represent mean ± SD, n=4 per group. *Significantly different (P<0.05) in comparison with FK506 aqueous suspension. **Significantly different (P<0.05) in comparison with Protopic, 0.1%, w/w. ***Significantly different (P<0.05) in comparison with FK506–NPs. ****Significantly different (P<0.05) in comparison with FK506–NIC solution. The concentration of FK506 in each formulation was 1 mg/mL.Abbreviations: FK506, tacrolimus; FK506–HA–Chol–NPs, tacrolimus-loaded hyaluronic acid–cholesterol nanoparticles; FK506–HA–Chol–NPs–NIC, tacrolimus-loaded hyaluronic acid–cholesterol nanoparticles containing nicotinamide; FK506–NIC complex, tacrolimus–nicotinamide complex; FK506–NPs, tacrolimus–nanoparticles complex; h, hours; SD, standard deviation.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4998035&req=5

f5-ijn-11-4037: In vitro skin percutaneous studies of FK506 from different vehicles.Notes: Data represent mean ± SD, n=4 per group. *Significantly different (P<0.05) in comparison with FK506 aqueous suspension. **Significantly different (P<0.05) in comparison with Protopic, 0.1%, w/w. ***Significantly different (P<0.05) in comparison with FK506–NPs. ****Significantly different (P<0.05) in comparison with FK506–NIC solution. The concentration of FK506 in each formulation was 1 mg/mL.Abbreviations: FK506, tacrolimus; FK506–HA–Chol–NPs, tacrolimus-loaded hyaluronic acid–cholesterol nanoparticles; FK506–HA–Chol–NPs–NIC, tacrolimus-loaded hyaluronic acid–cholesterol nanoparticles containing nicotinamide; FK506–NIC complex, tacrolimus–nicotinamide complex; FK506–NPs, tacrolimus–nanoparticles complex; h, hours; SD, standard deviation.
Mentions: As reported in previous studies, the application of NPs as the vehicle for percutaneous drug delivery achieved more retention of drugs in the skin for prolonging the residence time and targeting upper layer of skin.43,44 In the present study, we used HA–Chol–NPs as the carrier and NIC as the hydrotrope to prepare FK506–HA–Chol–NPs–NIC system and evaluate their effects on FK506 permeation into and across the skin. The cumulative permeated amount of FK506 was plotted versus time, and the retention of FK506 in the skin is shown in Figure 5 and Table 4. The commercial preparation (Protopic, 0.1%, w/v) and 0.1% (w/v) FK506 aqueous suspension were taken as the reference group and control group, respectively. As shown in Figure 5 and Table 4, the FK506 permeation from the NIC complex or HA–Chol–NPs was higher than that from Protopic or suspension after 24 hours of permeation, and there was no significant difference between Protopic and suspension (P>0.05). The cumulative permeated amount of FK506 from NPs or NIC complex was, respectively, 1.53-fold or 1.70-fold as that of Protopic, and the skin retention of FK506 from NPs or NIC complex was, respectively, 2.05-fold or 4.17-fold as that of Protopic. What is more, FK506 from NPs–NIC showed the highest permeation at all time points as compared with NPs or the NIC complex group. The cumulative permeated amount of FK506 was 13.38±2.26 μg/cm2 after 24 hours of permeation, which was significantly higher than that of the NIC complex, 6.60±2.27 μg/cm2 (P<0.05), or NPs alone, 5.96±1.05 μg/cm2 (P<0.05), and the FK506 retention in the skin from NPs–NIC presented the highest retention (2.39±0.53 μg/cm2) than NPs (0.84±0.14 μg/cm2) or the NIC complex (1.71±0.32 μg/cm2; P<0.05). The results indicated that either NPs carrier or NIC hydrotropy could enhance the permeation of FK506, and the combination of HA–Chol–NPs with NIC could synergistically enhance the permeation of FK506 into and through the skin.

View Article: PubMed Central - PubMed

ABSTRACT

Tacrolimus (FK506), an effective immunosuppressant for treating inflammatory skin diseases, hardly penetrates into and through the skin owing to its high hydrophobicity and molecular weight. The aim of this study was to develop a hybrid system based on nicotinamide (NIC) and nanoparticles (NPs) encapsulating FK506, such as FK506&ndash;NPs&ndash;NIC, for facilitating percutaneous delivery, which exploited virtues of both NIC and NPs to obtain the synergetic effect. Solubility and percutaneous permeation studies were carried out. The results showed that NIC could increase the solubility and permeability of FK506 and that 20% (w/v) NIC presented higher FK506 permeability and was thus chosen as the hydrotropic solution to solubilize FK506 and prepare FK506&ndash;NPs&ndash;NIC. Hyaluronic acid (HA) was chemically conjugated with cholesterol (Chol) to obtain amphiphilic conjugate of HA&ndash;Chol, which self-assembled NPs in 20% NIC solution containing FK506. The particle size, zeta potential, and morphology of NPs were characterized. The encapsulation efficiency and in vitro percutaneous permeation of NPs were evaluated in the presence and absence of NIC. The results demonstrated that hydrotropic solubilizing FK506 was readily encapsulated into NPs with a higher encapsulation efficiency of 79.2%&plusmn;4.2%, and the combination of NPs with NIC exhibited a significantly synergistic effect on FK506 deposition within the skin (2.39&plusmn;0.53 &mu;g/cm2) and penetration through the skin (13.38&plusmn;2.26 &mu;g/cm2). The effect of the combination of NPs with NIC on drug permeation was further visualized by confocal laser scanning microscope through in vivo permeation studies, and the results confirmed that NPs&ndash;NIC synergistically enhanced the permeation of the drug into the skin. The cellular uptake performed in HaCaT cells presented a promoting effect of NPs on cellular uptake. These overall results demonstrated that HA&ndash;Chol&ndash;NPs&ndash;NIC can synergistically improve the percutaneous delivery of FK506, and it is a novel potential strategy based on a nano-sized carrier for FK506 to treat skin diseases.

No MeSH data available.


Related in: MedlinePlus